KR20080098656A - Pharmaceutical formulations for aerosols comprising at least two active substances and at least one surfactant - Google Patents

Abstract

The present invention relates to novel pharmaceutical formulations for aerosols comprising two or more active ingredients and one or more surfactants, suitable for inhalation or nasal application. The present invention contains at least one surfactant together with an active agent combination of two or more active agents in the form of particles in which one or more active agents are dissolved and in the form of particles in which the other one or more active agents are suspended. A pharmaceutical formulation for propellant-containing quantitative aerosols containing rohydrohydrocarbons (HFA).

Quantitative aerosols, propellants, solutions, suspensions, active substance combinations, surfactants

Description

Pharmaceutical formulation for aerosols, comprising two or more active agents and at least one surfactant}

The present invention relates to novel pharmaceutical formulations for aerosols containing two or more active ingredients and one or more surfactants for inhalation or nasal application.

In propellant-driven metered dose inhalers, the active substance may be formulated as a solution or suspension. In the overwhelming majority, the aerosol formulations for quantitative inhalers are provided in the form of suspensions, especially when such formulations contain one or more active substances. Solution formulations are used only in a limited range. In this case the formulations generally contain only one active substance.

In general, the chemical stability of the active substance in suspension is significantly higher than in solution. In addition, the active substance can be more concentrated in suspension than in solution, meaning that higher doses can be obtained in the case of suspension formulations.

In suspension formulations, suspended particles accumulate over time (eg, upon storage) to form somewhat stable large aggregates or free flakes or they settle or float, or in the worst case exhibit particle growth. There is a significant disadvantage of serious damage to the chemical properties. The size or particle growth rate of the formed particles is influenced by the solution characteristics of the liquid phase. Thus, the intentional increase in polarity by moisture penetration during storage or the addition of co-solvents, for example, can have a disastrous effect on the quality of the final pharmaceutical product, especially when the suspended particles have a polar structural component. By adding surfactants, physical stabilization of the suspension can be achieved by reducing the deleterious effects of moisture and / or particle growth and allowing suspended particles to be retained in the suspension for longer periods of time.

Solution formulations are not naturally affected by the problem of increased particle size during separation processes such as sedimentation or precipitation. However, in this case the chemical degradation process represents a serious danger. Another disadvantage is that the limited solubility of the ingredients may interfere with the administration of high doses. Solvents that have proven particularly suitable in the past include chlorofluorocarbons TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetrafluoroethane). By adding a cosolvent, the solubility of the components can be increased. In addition, in solution formulations, additional measures generally have to be taken to chemically stabilize the dissolved components.

Propellant gases used to date are generally CFCs, for example TG 11 mentioned above. However, since CFCs have been involved in the destruction of the ozone layer, their production and use are being phased out. It is desirable to replace CFCs with special fluorinated hydrocarbons (HFAs), which cause less damage to the ozone layer but have completely different solution characteristics. For example, physicochemical properties such as toxicological profile and vapor pressure determine which HFAs are suitable for quantitative aerosols. Currently the most promising examples are TG 134a (1,1,2,2-tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane).

For treatment by inhalation, an aerosol formulation containing two or more active substance components may be desirable. The active substance is formulated as a solution uniformly as a solution or uniformly as a suspension at the required concentration, which is often associated with the problem of chemical stability of the attainable concentrations of the individual active substances. Important problems arise when one of the active substances cannot be suspended or is unstable in this kind of suspension formulation or when one of the active substances is chemically unstable or cannot be dissolved in the solution formulation, especially when HFA is used as propellant. do.

Accordingly, one object of the present invention is to develop formulations for quantitative aerosols containing at least one surfactant together with at least two active ingredients which overcome the above mentioned disadvantages.

Description of the Invention

Surprisingly, it has now been found that two or more active ingredients together with one or more surfactants can be formulated in one formulation side by side as a solvent and suspension and the formulation has improved properties.

The present invention relates to pharmaceutical preparations in the form of stable aerosol formulations comprising fluorinated hydrocarbons, in particular TG 134a and / or TG 227, as propellant gases, consisting of two or more active substances, wherein the one or more active substances Formulated as a solution and at least one active substance is formulated as a suspension and the formulation also contains at least one surfactant to enhance the properties of the formulation. The pharmaceutical preparations according to the invention are used for the treatment of diseases of the oral cavity and pharyngeal cavity and airways, for example asthma disease and inhalation of COPD.

The invention further relates to quantitative aerosols containing the pharmaceutical preparations according to the invention.

In one embodiment, medically useful combinations of one or more surfactants with two or more active agents are used for administration by the inhalation or nasal route.

The pharmaceutically active substance, substance formulation or mixture of substances used may be any inhalable compound, for example inhalable macromolecules described in EP 1 003 478. Preferably, the pharmaceutically active substance, substance formulation or mixture of substances to be inhaled is used to treat respiratory disease.

Particularly preferred in this category are anticholinergic agents, β-mimetics, steroids, phosphodiesterase IV inhibitors, LTD4-antagonists and EGFR-kinase inhibitors, antiallergic agents, ergot alkaloid derivatives, trytans, CGRP antagonists, Phosphodiesterase-V inhibitors and combinations of active substances of this kind, for example, pharmaceutical compositions selected from β-mimetic and anticholinergic or β-mimetic and antiallergic agents. In the case of a combination, at least one of the active substances contains chemically bound water. The anticholinergic-containing active substance is preferably used as a single agent or in the form of a combined formulation.

The following are specific examples of the active ingredient or salts thereof:

The anticholinergic agents used are preferably tiotropium bromide, oxytropium bromide, flute, optionally in the form of racemates, enantiomers or diastereomers and optionally in the form of solvates and / or solvates and / or hydrates. Fume bromide, ifpratropium bromide, glycopyrronium salt, trosfum chloride, tolterodine, trophenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, Scopin 2-fluoro-2,2-diphenylacetate-methobromide, topophenol 2-fluoro-2,2-diphenylacetate-methobromide, trophenol 3,3 ', 4,4'-tetrafluoro Robbenzylate Methobromide, Scopin 3,3 ', 4,4'-Tetrafluorobenzylate Methobromide, Trophenol 4,4'-Difluorobenzylate Methobromide, Scopin 4,4'-Difluoro Robenzylate Metrov Amide, trophenol 3,3'-difluorobenzylate methobromide, scopine 3,3'-difluorobenzylate methobromide, trophenol 9-hydroxy-fluorene-9-carboxylate methobromide, tro Phenol 9-fluoro-fluorene-9-carboxylate methobromide, scopine 9-hydroxy-fluorene-9-carboxylate methobromide, scopine 9-fluoro-fluorene-9-carboxylate methobromide, Trophenol 9-methyl-fluorene-9-carboxylate methobromide, scopin 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropin benzylate methobromide, 2,2-diphenylpropionate cyclopropyltropin methobromide, cyclopropyltropin 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropin benzylate methobromide, 2,2-diphenylpropionate cyclopropyltropin methobromide, cyclopropyltropin 9-hydroxy-xanthene-9-carboxylate metobromide, cyclopropyltropin 9-methyl-fluorene-9-carboxylate Methobromide, cyclopropyltropin 9-methyl-xanthene-9-carboxylate methobromide, Cyclopropyltropin 9-hydroxy-fluorene-9-carboxylate methobromide, methyl cyclopropyltropin 4,4'-difluorobenzylate methobromide, trophenol 9-hydroxy-xanthene-9-carboxyl Latemethobromide, scopine 9-hydroxy-xanthene-9-carboxylate methobromide, trophenol 9-methyl-xanthene-9-carboxylate methobromide, scopin 9-Methyl-Xanthene-9-carboxylate Methobromide, Trophenol 9-Ethyl-Xanthene-9-carboxylate Methobromide, Trophenol 9-Difluoromethyl-Xanthene-9-carboxylate Methobromide and Sco Pin 9-hydroxymethyl-xanthene-9-carboxylate methobromide.

The β-mimetic that can be used is preferably albuterol, bambuterol, optionally in racemic, enantiomeric or diastereomeric form and optionally in pharmaceutically acceptable acid addition salts, solvates and / or hydrate forms. , Bitolterol, broxaterol, carbuterol, clenbuterol, phenoterol, formoterol, hexoprelinin, ibuterol, indacaterol, isotarin, isoprenin, levosalbutamol, mabuterol, Meluadrin, metaproterenol, orcifrelinin, pirbuterol, procaterol, reproterol, limiterol, lithodrin, salmeterol, salmephamol, sotherenote, sulfonterol, tiaramid, terbu Tallinn, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl Amino-hexyloxy} -butyl) -benzenesulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1 H - Nolin-2-one, 4-hydroxy-7- [2-{[2-{[3- (2-phenylethoxy) propyl] -sulfonyl} ethyl] -amino} ethyl] -2 (3H)- Benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- ( 4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy -3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino ] Ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2 , 4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and 1- ( 4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol.

The steroids that may be used are preferably prednisolone, prednisone, butyxocortpropionate, RPR-, optionally in racemic, enantiomeric or diastereomeric form and optionally in salt and derivative, solvate and / or hydrate form. 106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, lopleponide, ST-126, dexamethasone, (S) -fluoromethyl 6α, 9α- Difluoro-17α-[(2-ruranylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothionate, (S)- (2-oxo-tetrahydro-furan-3S-yl) 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene- 17β-carbothionate and etiprenol-dichloroacetate (BNP-166).

PDE IV inhibitors that can be used are preferably enpropyline, theophylline, optionally in racemic, enantiomeric or diastereomeric forms and optionally in pharmacologically acceptable acid addition salts, solvates and / or hydrate forms, Loflumilast, ariflo (silomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- (3,5-dichloro-1- Oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, fumapentin, (-) p-[(4aR *, 10bS *)-9-ethoxy -1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide , (R)-(+)-1- (4-bromobenzyl) -4-[(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy- 4-methoxyphenyl) -1- (4-N '-[N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4 -(3-cyclopentyloxy-4-methoxyphenyl) Rohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-one, cis [4-cyano -4- (3-cyclopropyl-methoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol], (R)-(+)-ethyl [4- (3-cyclopentyloxy-4-meth Oxyphenyl) pyrrolidine-2-ylidene] acetate, (S)-(-)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, Arophylline, Artizora, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM- 58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-tria Zolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4-c] -1,2 , 4-triazolo [4,3-a] pyridine.

LTD4-antagonists which can be used are preferably in the form of racemates, enantiomers or diastereomers, optionally in the form of pharmacologically acceptable acid addition salts and optionally in the form of salts and derivatives, solvates and / or hydrates, Montelukast, 1-(((R)-(3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy- 2-propyl) phenyl) thio) methylcyclopropane-acetic acid, 1-(((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridine-5-) Yl)-(E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) -methyl) -cyclopropane-acetic acid, franlukast, Lucast, [2-[[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321.

EGFR-kinase inhibitors that can be used are preferably cetuximab, tra, optionally in racemic, enantiomeric or diastereomeric forms, optionally in the form of pharmacologically acceptable acid addition salts, solvates and / or hydrates. Stuzumab, ABX-EGF, Mab ICR-62, 4-[(3-chloro-4-fluorophenyl) amino] -6-{[4- (morpholin-4-yl) -1-oxo-2 -Buten-1-yl] -amino} -7-cyclopropylmethoxy-quinazolin, 4-[(R)-(1-phenyl-ethyl) amino] -6-{[4- (morpholine-4- Yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6-{[ 4-((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-[(S)-(tetrahydrofuran- 3-yl) oxy] -quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholine-4 -Yl) -ethoxy] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-({4- [N- (2-meth Methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazolin, 4-[(R)-(1-phenyl-ethyl ) Amino] -6-({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylme Methoxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo -2-buten-1-yl} amino) -7-cyclopentyloxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-{[4- (N, N-dimethyl Amino) -1-oxo-2-buten-1-yl] amino} -7-[(R)-(tetrahydrofuran-2-yl) methoxy] -quinazolin, 4-[(3-ethynyl- Phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazolin, 4-[(R)-(1-phenyl-ethyl) amino] -6- (4-hydroxy-phenyl ) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl) amino] -6-{[4- (N, N-dimethyl Amino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4-[(R)-(1-phenyl- Ethyl) amino] -6-{[4-((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-meth Methoxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-{[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl]- Amino} -7-[(tetrahydrofuran-2-yl) methoxy] -quinazolin, 4-[(3-ethynyl-phenyl) amino] -6-{[4- (5,5-dimethyl-2 -Oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- { 2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro Rho-phenyl) amino] -6- (trans-4-amino-cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (Tetrahydropyran-3-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-ple Oro-phenyl) amino] -6- {1-[(morpholin-4-yl) carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazolin, 4-[(3- Chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {trans-4-[(mor Polin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {1 -[(Piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N-[(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4- [(3-chloro-4-fluoro-phenyl) amino] -6 -(Trans-4-ethanesulfonylamino-cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1 Methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazolin, 4-[(3-ethynyl-phenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N- [(Piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro -Phenyl) amino] -6- {cis-4-[(morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazolin, 4-[(3- Chloro-4-fluoro-phenyl) amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy- Quinazolin, 4-[(3-ethynyl-phenyl) amino] -6- (1- Cetyl-piperidin-4-yloxy) -7-methoxy-quinazolin, 4-[(3-ethynyl-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazolin, 4-[(3-ethynyl-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazolin, 4-[(3-ethynyl-phenyl) amino] -6- {1-[(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- {1-[(N-methyl-N-2-methoxyethyl-amino) carbonyl] -piperidin-4-yljade Cy} -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy -Quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy ] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [si S-4- (N-acetyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methylamino-cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [trans 4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- ( Trans-4- {N-[(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazolin, 4-[(3- Chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-[(S)-(tetrahydro Furan-2-yl) methoxy] -quinazolin, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy)- 7-methoxy- Nazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazolin and 4- [ From (3-chloro-4-fluoro-phenyl) amino] -6- {1-[(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline Is selected.

Acid addition salts which can be formed with the compound and pharmacologically acceptable acids are, for example, hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate , Hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, Hydrophosphate, hydrofumarate and hydromethanesulfonate.

Examples of anti-allergic agents are disodium chromoglycate, nedochromyl.

Examples of ergot alkaloids are dihydroergotamine, ergotamine.

Examples of materials suitable for inhalation include medicaments, pharmaceutical formulations and mixtures containing the active substances and salts and esters thereof described above and combinations of these active substances, salts and esters.

In the preparations according to the invention which of the above-mentioned active substances are formulated as solutions and which are formulated as suspensions depends on the specific combination of active substances and can be determined relatively quickly by solution and suspension experiments.

In a preferred embodiment, one or more of the following active substances are suspended: budesonide, chromoglycinic acid, nedocromyl, reproterol and / or salbutamol (albuterol) or esters, salts derived from these compounds and And / or solvates. One or more of the following materials are dissolved: beclomethasone, phenoterol, ifpratropium bromide, orsiprenaline and / or oxytropium bromide, N-[[2,2-dimethyl-4- (2- Oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide or esters, salts derived from these compounds and // Or solvates. Preference is given to embodiments containing two different active substances.

Preferably, the pharmaceutical formulation is beclomethasone, budesonide, chromoglycinic acid, phenoterol, flunisolide, fluticasone, ifpratropium, nedocromyl orsiprenaline, oxytropium bromide, lef Roterol, salbutamol, salmeterol (albuterol), terbutalin, N-[[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoro Methyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide, esters, salts and / or solvates thereof.

A particularly preferred embodiment of the pharmaceutical formulation contains dissolved ispratropium bromide monohydrate, in particular together with salbutamol sulfate (albuterol sulfate) as the active substance suspended.

In all embodiments, the active substance is used in a therapeutically effective amount, that is, in an amount capable of providing successful treatment. The concentration of the active substance and the volume delivered per spray jet are adjusted so that one or only several spray sprays deliver a medically necessary or recommended amount of the active substance.

One embodiment relates to formulations in which suspended particles are stabilized by the addition of surfactants. This has the advantage that the particle size remains pharmaceutically stable and acceptable even over long periods of time, for example during storage. Particle sizes of 20 μm or less are preferred, particle sizes of 5 to 15 μm are most particularly preferred, most preferably not exceeding 10 μm. The advantage of these particle sizes is that the particles are small enough to penetrate deep into the lungs, but not small enough to be spit out again with the exchanged air.

Suitable surfactants include all pharmacologically acceptable materials having lipophilic hydrocarbon groups and one or more functional hydrophilic group (s). C _5-20 - fatty alcohols, C _5-20 - fatty acids, C _5-20 -, particularly suitable fatty acid esters, lecithin, glycerides, propyleneglycol esters, polyoxyethylene, polysorbate, sorbitan esters and / or carbohydrates Do. C _5-20 - fatty acids, propylene glycol diesters, and / or C _5-20 - triglycerides of fatty acids and / or sorbitan are preferred, C _5-20 - sodium or potassium salts of fatty acids, oleic acid and sorbitan -Di- or trioleate, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene sorbitan ester, polyoxyethylene glycerol ester, polyoxyethylene fatty acid ester, polyoxypropylene fatty acid ester, polyoxyethylene / polyoxy Particular preference is given to propylene block copolymers, alkylpolyglycosides, benzalkonium chloride and / or cetylpyridinium chloride.

Most particularly preferred are polyvinylpyrrolidone K25 (Povidone 25 ^R ), polyoxyethylene-20-sorbitan monolaurate, polyoxyethyleneglycerol trioleate or combinations of these surfactants. Especially preferred according to the invention are polyoxyethylene-20-sorbitan monolaurate and polyoxyethyleneglycerol trioleate which are commercially available and obtainable under the trade names Tween ^R 20 and Tagat ^R TO V.

The surfactant is preferably present in the formulation according to the invention at a concentration of 0.001 to 5% (m / m), particularly preferably 0.01 to 3% (m / m).

In a particularly preferred embodiment of the invention, at least one, preferably one, of the abovementioned surfactants is from 0.02 to 0.2% (m / m), preferably from 0.05 to 0.15% (m / m), in particular 0.1% (m / m).

In another preferred alternative embodiment of the invention, at least one, preferably one of the abovementioned surfactants is 0.3 to 2.5% (m / m), preferably 0.4 to 2% (m / m), particularly preferably Is present at a concentration of 0.5 to 1.5% (m / m), more preferably 0.75 to 1.25% (m / m), in particular 1.0% (m / m).

A further advantage of these surfactants is that such surfactants can also be used as valve lubricants. Thus, one aspect relates to formulations in which the surfactant is added as a valve lubricant.

In another embodiment, the solubility of the active substance (s) to be dissolved is increased by the addition of a cosolvent. This has the advantage that the active substance (s) to be dissolved can be formulated in high concentrations. The addition of cosolvents should ensure that the liquid phase does not exceed the threshold polarity threshold, above which one of the disadvantages arises in suspended particles of the active substance.

Suitable cosolvents are pharmacologically acceptable alcohols such as ethanol, ester or water or mixtures thereof, with ethanol being preferred. The concentration of cosolvent based on the entire formulation may be 0.0001 to 50% (m / m), preferably 0.01 to 25% (m / m). In a preferred embodiment, the concentration of cosolvent is 1-20% (m / m), preferably 5-15% (m / m). Most particularly preferred are formulations according to the invention with a concentration of cosolvent of 8 to 12% (m / m), in particular 10% (m / m).

Concentrations specified within the scope of the present invention are always in mass% [% m / m] based on the mass of the entire formulation.

In other embodiments, other conventional propellant gases are added to the HFA propellant gas. This added propellant gas may be, in addition to other fluorinated hydrocarbons, saturated lower hydrocarbons such as propane, butane, isobutane or pentane, provided the mixture is pharmacologically safe.

In one embodiment, stabilizers are added to the formulation to advantageously affect the pharmaceutical stability of the active substance over a long period of time, eg, during storage. In the context of the present invention, the term stabilizer is used to prevent or delay chemical changes to the individual components, in particular to the active substance, as well as to other additives as a result of, for example, secondary reactions or degradation, thereby increasing the durability and A substance that extends its useful life or prevents biological contamination. In this sense, preferred stabilizers are substances which affect the pH value of the liquid phase, for example acids and / or salts thereof. Particularly suitable acids are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid and salts thereof. Examples of suitable fungicides, fungicides and the like include benzalkonium chloride and ethylenediamine tetraacetate. Citric acid is most preferred. The concentration of stabilizer mentioned above is in the range of 0.0001 to 0.02% (m / m), preferably in the range of 0.0005 to 0.01% (m / m). Particularly preferred formulations according to the invention contain the abovementioned stabilizers at concentrations of 0.001 to 0.008% (m / m), concentrations of 0.002 to 0.006% (m / m), in particular about 0.004% (m / m) Is particularly important according to the invention.

Particularly preferred embodiments include suspended salbutamol sulfate (albuterol sulfate), dissolved ypratropium bromide, ethanol as cosolvent and citric acid as stabilizer. These particularly preferred formulations according to the invention preferably contain 0.1 to 0.3% (m / m) of the active substance salbutamol sulfate, particularly preferably 0.15 to 0.25% (m / m), more preferably 0.18 to 0.22 at a concentration of% (m / m). These particularly preferred formulations according to the invention also contain ypratropium bromide monohydrate at a concentration of preferably 0.02 to 0.05% (m / m), particularly preferably 0.03 to 0.04% (m / m). Particular preference is given to the present invention in which the ratio of the two active substances salbutamol sulphate and ifpratropium bromide monohydrate at the aforementioned concentrations is in the range from 5: 1 to 6: 1, particularly preferably in the range from 5.5: 1 to 5.9: 1. Composition according to the invention. Particular preference is given to compositions according to the invention in which the ratio of the two active substances salbutamol sulphate and ifpratropium bromide monohydrate at this concentration is in the range of 5.60: 1 to 5.85: 1, in particular in the range of 5.70: 1 to 5.80: 1. .

In all embodiments, the formulation is transferred to a metal container suitable for quantitative aerosol, which is sealed with a suitable metering valve. Examples of suitable metal containers include stainless steel one-piece cans (DIN 1.4539) (Presspart Manufacturing Ltd., Blackburn UK) having a nominal volume of 17 ml. Suitable metering valves include, for example, BK 357 or BK 361 (Bespak Europe Ltd., King's Lynn, UK).

The quantitative aerosols according to the invention are preferably group beclomethasone, budesonide, chromoglycinic acid, phenoterol, flunisolide, fluticasone, ifpratropium, nedocromyl, orsiprelinin, oxy Tropium bromide, leproterol, salbutamol, salmeterol (albuterol), terbutalin, N-[[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl)- Pharmaceuticals containing a combination of active substances selected from 6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide, esters, salts and / or solvates thereof Contains pharmaceutical preparations.

Most particularly preferably, the quantitative aerosols according to the invention contain pharmaceutical preparations containing the active substance salbutamol sulfate (albuterol sulfate) and ypratropium bromide monohydrate.

Example 1:

Example 2:

Example 3:

Example 4:

Example 5:

Example 6:

Example 7:

Example 8:

Example 9:

Example 10:

Example 11:

Example 12:

Claims (24)

Characterized in that it contains at least one surfactant together with a combination of two or more active substances, at least one active substance is in dissolved form and the other at least one active substance is in the form of suspended particles, A pharmaceutical formulation for propellant-driven quantitative aerosols having fluorinated hydrocarbons (HFA) as propellant. 2. A pharmaceutical formulation according to claim 1, wherein the active substance combination consists of two active substances. The pharmaceutical formulation according to claim 1 or 2, wherein the propellant is TG 134a and / or TG 227. The pharmaceutical preparation according to any one of claims 1 to 3, which contains a cosolvent. 5. The pharmaceutical formulation of claim 4, wherein the cosolvent contains one or more pharmacologically acceptable alcohols, pharmacologically acceptable esters, water or mixtures thereof. The pharmaceutical formulation according to claim 4, wherein the cosolvent is ethanol. The pharmaceutical formulation according to claim 4, 5 or 6, wherein the cosolvent is present at a concentration of 0.0001 to 50% (m / m) based on the total formulation. The pharmaceutical preparation according to claim 7, wherein the cosolvent is present at a concentration of 5 to 15% (m / m), preferably 8 to 12% (m / m), based on the total formulation. The pharmaceutical formulation according to any one of claims 1 to 8, which is stabilized by a stabilizer. The pharmaceutical formulation of claim 9, wherein the stabilizer contains one or more acid (s) and / or salt (s) thereof. The pharmaceutical composition of claim 9, wherein the stabilizer or stabilizers contain hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride and / or ethylenediamine tetraacetate and / or salts thereof. Formulation. The pharmaceutical formulation of claim 9 wherein the stabilizer is citric acid. 13. The method according to any one of claims 9, 10, 11 or 12, wherein the stabilizer is from 0.0001 to 0.02% (m / m), preferably from 0.0005 to 0.01% (m / pharmaceutical formulation, characterized in that it is present at a concentration of m). The pharmaceutical formulation of claim 13, wherein the stabilizer is present at a concentration of 0.0001 to 0.008% (m / m), preferably 0.002 to 0.006% (m / m), based on the total formulation. The pharmaceutical formulation according to any one of claims 1 to 14, which contains at least one surfactant. The method of claim 15, wherein the surfactant is a sodium or potassium salt of C _{5-20 -fatty} acid, oleic acid, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene sorbitan ester, polyoxyethylene glycerol ester, polyoxyethylene fatty acid A pharmaceutical formulation characterized in that the ester, polyoxypropylene fatty acid ester, polyoxyethylene / polyoxypropylene block copolymer, alkylpolyglycoside, benzalkonium chloride and / or cetylpyridinium chloride or combinations thereof. The pharmaceutical formulation of claim 15 wherein the surfactant is polyvinylpyrrolidone K25, polyoxyethylene-20-sorbitan monolaurate or polyoxyethyleneglycerol trioleate or a combination of these surfactants. 18. The surfactant according to any one of claims 15, 16 or 17, characterized in that the surfactant is present at a concentration of 0.001 to 5% (m / m), preferably 0.01 to 3% (m / m). Pharmaceutical preparations. The pharmaceutical formulation of claim 18, wherein the surfactant is present at a concentration of 0.02 to 0.2% (m / m), preferably 0.05 to 0.15% (m / m). The surfactant according to claim 18, wherein the surfactant is 0.3 to 2.5% (m / m), preferably 0.4 to 2% (m / m), particularly preferably 0.5 to 1.5% (m / m), more preferably A pharmaceutical formulation, characterized in that it is present at a concentration of 0.75 to 1.25% (m / m). 21. The method according to any one of claims 1 to 20, wherein the active substance combination is an anticholinergic agent, β-mimetics, steroids, phosphodiesterase IV inhibitors, LTD4-antagonists and EGFR-kinase inhibitors, antiallergic And, at least one active substance selected from ergot alkaloid derivatives, triptans, CGRP antagonists and phosphodiesterase-V inhibitors. 22. The active material combination according to any one of claims 1 to 21, wherein the active substance combination is beclomethasone, budesonide, chromoglycinic acid, phenoterol, flunisolide, fluticasone, ifpratropium, nedocromil Orsiprelinin, oxytropium bromide, leproterol, salbutamol, salmeterol (albuterol), terbutalin, N-[[2,2-dimethyl-4- (2-oxo-2H-pyridine- 1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide, esters, salts and / or solvates thereof Pharmaceutical formulations. The pharmaceutical formulation according to any one of claims 1 to 22, which contains salbutamol sulfate (albuterol sulfate) and ypratropium bromide monohydrate as active substance combinations. A quantitative aerosol containing a pharmaceutical formulation according to any one of claims 1 to 23.